CXCL12/CXCR4 signaling mediated ERK1/2 activation in spinal cord contributes to the pathogenesis of postsurgical pain in rats

Background: It has been demonstrated that upregulation of CXCL12 and CXCR4 in spinal cord involve in the pathogenesis of neuropathic, inflammatory and cancer pain. However, whether CXCL12/CXCR4 signaling contributes to postsurgical pain remains unknown. The aim of the present study is to investigate the role of CXCL12/CXCR4 signaling in the genesis of postsurgical pain and the underlying mechanism. Results: Plantar incision ( PI) in rat hind paw resulted in increased expressions of CXCL12 and CXCR4 in spinal dorsal horn. Double immunofluorescence staining revealed that CXCL12 expressed in neurons and astrocytes, and CXCR4 exclusively co-localized with neuronal cells. Prior to administration of AMD3100, a specific antagonist of CXCR4, or CXCL12 neutralizing antibody intrathecally attenuated PI-induced mechanical allodynia and thermal hyperalgesia. PI also augmented the phosphorylation of NF-kappa B p60 in spinal cord. Pre intrathecal injection (i.t.) of PDTC, a specific NF-kappa B activation inhibitor, alleviated PI-induced postsurgical pain, and reduced the expression of CXCL12 in spinal cord. Correlated with the upregulation of CXCL12 and CXCR4, PI also resulted in an increased phosphorylation of ERK1/2 and Akt in spinal cord. Prior to i.t. administration of AMD3100 prevented ERK, but not Akt, activation in spinal cord. Rats given a repetitive i.t. PD98059, a specific ERK kinase inhibitor, started 30 min before surgery also ameliorate PI-induced mechanical and thermal pain hypersensitivity. Conclusion: Our results suggests that PI-induced activation of NF-kappa B signaling may mediate upregulation of CXCL12 in spinal cord, and CXCL12/CXCR4 signaling via ERK activation contributes to the genesis of postsurgical pain.